One of the limitations on the use of blood in an emergency setting is a requirement to type and cross-match the blood to minimize the risk of transfusion rejection. Saline cross-matching may require at least 10 minutes and a complete type and cross-match can take up to an hour. Furthermore, the risk of HIV transmission has been estimated to be 1 in 500,000 units of blood and the risk of hepatitis C transmission has been estimated to be 1 in 3,000 units. The safety of blood supply is an issue in developing countries, where the risk of infectious disease transmission is relatively higher. Up to 25% of the blood is discarded in developing countries because of the presence of infectious disease. Hence, there are pressing factors to find a potential blood substitute that avoids the disease transmission and provides rapid response to improve chances of survival.
The examples of two “blood substitute” categories are volume expanders and oxygen therapeutics. Volume expanders are inert and merely increase blood volume. Oxygen therapeutics mimics human blood's oxygen transport ability. Oxygen therapeutics can be divided in two categories based on transport mechanism: perfluorocarbon based, and hemoglobin (protein) based. In hemoglobin-based products, pure hemoglobin separated from red blood cells may not be useful since it may cause renal toxicity and it may have unsuitable oxygen transport characteristics when separated from red blood cells.
Some of the characteristics of a blood substitute are: virus-free, non-toxic, non-immunogenic, satisfactory oxygen carrying capacity and circulatory persistence to permit effective oxygenation of tissues, long shelf life, storage at room temperature, avoids disease transmission, no requirement of blood typing, and deployable for use by first responders such as, paramedics, military medics on front lines etc. These characteristics provide a rapid response to blood loss and can improve chances of survival.
The present invention disclosed herein provides compositions and methods for deoxygenated, endotoxin free, stroma free, carboxymethylated cross-linked tetrameric hemoglobin.